Project Summary/Abstract Posttraumatic stress disorder (PTSD) is one of the most prevalent, chronic, and disabling psychiatric disorders in combat veterans. Despite some advances in characterizing biological factors associated with PTSD, the neurobiology of this disorder remains incompletely understood. Elucidation of the neurobiology of PTSD is important, as it has the potential to improve understanding of the etiology and inform the development of more targeted, mechanism-based, and personalized treatments for this disorder. To this end, we propose a state-of-the-art, multi-modal functional magnetic resonance imaging-positron emission tomography (fMRI-PET) study that will determine, for the first time, functional neural and molecular (i.e., cannabinoid type 1 [CB1] receptor) underpinnings of fear reversal learning, a core feature of PTSD characterized by the ability to flexibly control and maneuver acquired fear responses in combat veterans presenting with the full dimensional spectrum of combat-related PTSD symptoms. Given that fear reversal learning is impaired in PTSD and contributes to the chronicity of this disorder, characterization of neurobiological factors that underlie its component processes can inform both the etiology and personalization of treatments for this disorder. Upon returning from the battlefield, why is it that some combat veterans develop PTSD but others do not? A predominant theory is that individuals with PTSD are markedly impaired in their ability to extinguish and reverse fear learning. During fear reversal learning, an individual first acquires a conditioned response to a fear predictive cue while ignoring another cue that predicts nothing (acquisition phase). Then, the individual flexibly switches the fear response between cues, when the conditioned one does not predict the fearful outcome anymore, but the previously safe one does (reversal phase). As in combat and other stressful situations, fear reversal learning engages two processes simultaneously?learning what to fear and learning what is safe?which in turn helps to promotes flexible adaptation to fear.. While behavioral models of fear reversal learning in PTSD are well established, scarce research has examined the neurobiology of this core component of this disorder. This information is essential to understanding the neurobiology of how combat veterans process fear-related information in complex and dynamic situations, particularly as they adapt to civilian life after deployment. To address this gap in the literature, we propose a multi-modal fMRI-PET study of the neural correlates of fear reversal learning in combat veterans presenting with the full dimensional spectrum of combat-related PTSD symptoms. The proposed study, which directly addresses the CSR&D high priority area of PTSD research, will generate novel insights into the neural, molecular, and behavioral underpinnings of fear reversal learning in combat-related PTSD. By employing PET molecular imaging methods with the [11C]OMAR CB1 tracer in combination with advanced fMRI methods, results of the proposed study will inform: (1) understanding of the neurobiological etiology of fear reversal learning in combat-related PTSD; and (2) development of novel, mechanism-based treatments that target the endocannabinoid system, which may ultimately help promote more adaptive fear reversal learning in combat veterans with PTSD.